Urine lipoarabinomannan glycan in HIV-negative patients with pulmonary tuberculosis correlates with disease severity

Abstract

An accurate urine test for pulmonary tuberculosis (TB), affecting 9.6 million patients worldwide, is critically needed for surveillance and treatment management. Past attempts failed to reliably detect the mycobacterial glycan antigen lipoarabinomannan (LAM), a marker of active TB, in HIV-negative, pulmonary TB–infected patients’ urine (85% of 9.6 million patients). We apply a copper complex dye within a hydrogel nanocage that captures LAM with very high affinity, displacing interfering urine proteins. The technology was applied to study pretreatment urine from 48 Peruvian patients, all negative for HIV, with microbiologically confirmed active pulmonary TB. LAM was quantitatively measured in the urine with a sensitivity of >95% and a specificity of >80% (n = 101) in a concentration range of 14 to 2000 picograms per milliliter, as compared to non-TB, healthy and diseased, age-matched controls (evaluated by receiver operating characteristic analysis; area under the curve, 0.95; 95% confidence interval, 0.9005 to 0.9957). Urinary LAM was elevated in patients with a higher mycobacterial burden (n = 42), a higher proportion of weight loss (n = 37), or cough (n = 50). The technology can be configured in a variety of formats to detect a panel of previously undetectable very-low-abundance TB urinary analytes. Eight of nine patients who were smear-negative and culture-positive for TB tested positive for urinary LAM. This technology has broad implications for pulmonary TB screening, transmission control, and treatment management for HIV-negative patients.

Adoption and uptake of the lateral flow urine LAM test in countries with high tuberculosis and HIV/AIDS burden: current landscape and barriers

“…The barriers identified in our questionnaire, along with advocacy reports by groups such as TAG and MSF, can help policy makers, country governments, and donors build better strategies for Alere-LAM implementation and scale-up. These questionnaire results should help guide efforts to develop higher-sensitivity urine LAM tests [33][34][35] and rapidly roll them out, as country adoption of improved products must anticipate challenges from the field.…”

Point-Of-Care Urine LAM Tests for Tuberculosis Diagnosis: A Status Update

“…Several recent research reports indicate that lower detection limits will translate into higher diagnostic sensitivity and demonstrate necessary measures to improve the analytical sensitivity. First, Paris et al developed a sample preparation device that concentrates antigens and detects LAM down to 14 pg/mL, resulting in 95% sensitivity at 80% specificity in a study of 48 HIV-negative TB-positive subjects and 58 TB-negatives with other respiratory diseases and healthy controls [51]. Shapiro et al developed a device to concentrate and detect LAM in urine and reported 52% sensitivity in HIV-negative TB-positive persons at 67% specificity in a study with 93 patients [52].…”

Urine Tests for Diagnosis of Infectious Diseases and Antibiotic-Resistant Pathogens

“…With lipoarabinomannan (cell wall glycolipid of Mycobacterium tuberculosis) being secreted in the urine, several assays and tools have been developed to detect this marker of infection. However, no urine test until now is sensitive enough to be adopted for routine use [17,18].…”

“…In infectious disease field, urine tests are applied in diagnosing urinary tract infections (UTI) [11][12][13]. Further, several other infections can be diagnosed by urine tests at different levels [14] including community-acquired pneumonia (CAP) [15], legionellosis [16], tuberculosis [17,18], congenital cytomegalovirus (CMV) infection [19], and dengue virus [20,21], and recently, several papers suggest the high value of urinalysis in the detection of Zika virus [22,23]. Parasites can also be diagnosed from the urine by detection of urinary egg, for example, diagnosis of Schistosoma haematobium (S. haematobium) [24].…”